The effect of beta agonists and corticosteroids on bronchial reactivity in asthma

Vathenen, Arumugan Santhire (1989) The effect of beta agonists and corticosteroids on bronchial reactivity in asthma. University of Southampton, Doctoral Thesis.

Abstract

The mechanisms underlying bronchial hyperreactivity, a characteristic feature of asthma, and the mechanisms by which drugs alter bronchial reactivity are still poorly understood. Detailed studies of the effect of beta₂ agonists and corticosteroids, the two most effective drugs used in the treatment of asthma, on bronchial reactivity form the basis of this thesis. Two double blind, randomised, cross-over studies were carried out in asthmatic subjects to determine the time course of change in bronchial reactivity, measured as the provocative dose of histamine causing a 20% fall in FEV₁ (PD₂₀), after short term (1 day) and longer term (14 days) treatment with an inhaled beta₂ agonist. In the first study in 8 subjects, inhaled terbutaline 500 and 2000 ug given three times during one day protected against histamine induced bronchoconstriction (change in PD₂₀ of 2.2 and 3.5 doubling doses after 1 hour, respectively), and the increase in PD₂₀ remained elevated relative to placebo throughout the day and overnight. In the second study 8 subjects received placebo or inhaled terbutaline 750 ug three times a day for 14 days with measurements of PD₂₀ at intervals on days 1 and 14 and after cessation of treatment on day 15. The protection afforded by terbutaline against histamine induced bronchoconstriction on day 14 was less than that on day 1 by 40% in the morning and 82% in the afternoon. On day 15, PD₂₀ was lower after cessation of terbutaline than after placebo with a maximum difference of 1.5 doubling doses of (DD) histamine 23 hours after cessation of treatment. Thus treatment with terbutaline for one day did not result in any rebound increase in bronchial reactivity whereas treatment for two weeks impaired the ability of terbutaline to protect against histamine induced bronchoconstriction, and was followed by a rebound increase in bronchial reactivity after cessation of treatment. In a further study forty asthmatic subjects received inhaled budesonide 800 ug or placebo twice daily for 6 weeks in a double blind parallel group design. The first dose of budesonide caused an increase in FEV₁ and PD₂₀ of 0.21 and 1.0 DD of histamine. There was a further increase in FEV₁ and PD₂₀ over the 6 weeks in the budesonide group, the maximum increases relative to placebo (0.53 1, 3.4 DD) being recorded 6 hours after the last dose on day 42. Following cessation of treatment FEV₁ and PD₂₀ returned to placebo values by 1 week. Changes in daily PEF recordings, symptom scores and beta₂ agonist inhaler followed a similar pattern. Change in bronchial reactivity (measured as % fall in FEV₁ following a fixed dose of stimulus) following 6 weeks budesonide was similar for histamine, exercise and eucapnic dry air hyperventilation with decreases in the % fall from 24.5% to 7%, 23.5% to 8.4% and 26.6% to 5% respectively. Thus inhaled budesonide caused a progressive decrease in bronchial reactivity with regular treatment and caused a similar degree of protection against histamine, exercise and dry air hyperventilation; the decrease in bronchial reactivity was however short-lived, lasting less than a week after cessation of treatment.

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